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At least 469 records · Page 26Linked to original sources
PubMed2006

Glucose-deprived HT-29 human colon carcinoma cells are sensitive to verrucosidin as a GRP78 down-regulator.

Glucose deprivation, a feature of poorly vascularized solid tumors, activates the unfolded protein response (UPR) which is a stress-signaling pathway in tumor cells that is associated with the molecular chaperone GRP78 and induction of GRP78 has been shown to protect them against programmed cell death. Thus, targeting glucose-deprived conditions may be a novel strategy in anticancer drug development. Based on that, we established a novel screening program for chaperone modulators that preferentially cytotoxic activity in cancer cells under glucose-deprived conditions. During the course of our screening system, we recently isolated an active compound, 326-2, from Penicillium verrucosum var. cyclopium and identified it as a down-regulator of the grp78 gene. As expected, 326-2 inhibited the expression of the GRP78 promoter under glucose-deprived conditions in a dose-dependent manner with an IC(50) value of 50nM. Furthermore, 326-2 was identified as verrucosidin, a pyrone-type polyketide, by ESI-MS analyses and various NMR spectroscopic methods. We found that verrucosidin prevents UPR-induced expression of protein, such as GRP78, whose expression is induced by glucose-deprived or by 2-deoxyglucose; this effect is not seen under normal growth conditions. The GRP78-inhibitory action of verrucosidin was dependent on strict hypoglycemic conditions and resulted in selective cell death of glucose-deprived HT-29 human colon cancer cells.

Cell Survival↗
PubMed1996

Anticonvulsive action of (+/-)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites.

Kava pyrones are constituents of the intoxicating pepper (Piper methysticum Forst), which has been shown to be anticonvulsive. The question of how the excitability of neurons is affected was investigated by determining the interaction of (+/-)-kavain with epitopes (site 1, site 2) of voltage-dependent Na+ channels and the action of (+/-)-kavain on 4-aminopyridine-stimulated synaptosomes as model of repetitive firing neurons. [3H]Saxitoxin and [3H]batrachotoxin were used for radioligand-binding assays performed with synaptosomal membranes. Gultamate released from 4-aminopyridine-stimulated cerebrocortical synaptosomes and the cytosolic concentrations of Na+ and Ca2+ ([Na+]i, [Ca+]i) were detected fluorometrically by using an enzyme-linked assay, sodium-binding benzofuranisophthalate (SBFI) and Fura-2, respectively. (+/-)-Kavain failed to compete with [3H]saxitoxin up to 400 mumol/l but dose-dependently suppressed binding of [3H]batrachotoxin with an IC50 value of 88 mumol/l (Ki = 72 mumol/l) although displacement of [3H]batrachotoxin was restricted to 33% of control at 400 mumol/l (+/-)-kavain. In stimulated synaptosomes, 5 mmol/l 4-aminopyridine provoked an increase in [Na+]i and [Ca2+]i by 9 mmol/l Na+ and 235 nmol/l Ca2+. Comparable to the reduction in [3H]batrachotoxin binding, 400 mumol/l (+/-)-kavain suppressed the increase in [Na+]i and [Ca2+]i to 38 and 29% of control, respectively. Consistent with the increase in [Na+]i and [Ca2+]i, 5 mmol/l 4-aminopyridine provoked glutamate release (rate: 38 pmol/s*mg protein) which was dose-dependently diminished to 60% of control by 400 mumol/l (+/-)-kavain. KCl depolarization (40 mmol/l) provoked an increase in [Ca2+]i and glutamate release almost identical to the responses elicited by 4-aminopyridine but 400 mumol/l (+/-)-kavain suppressed only the rate of glutamate release by 9% of control. The data suggest an interaction of (+/-)-kavain with voltage-dependent Na+ and Ca2+ channels, thereby suppressing the 4-aminopyridine-induced increase in [Na+]i, [Ca2+]i and the release of endogenous glutamate.

4-Aminopyridine↗
PubMed2002

Chemical and anti-platelet constituents from Formosan Zanthoxylum simulans.

A pyrrole alkaloid, pyrrolezanthine [5-hydroxymethyl-1-[2-(4-hydroxyphenyl)-ethyl]-1H-pyrrole-2-carbaldehyde]; a lignan, (-)-simulanol [4- [3-hydroxymethyl-5-((E)-3-hydroxypropenyl)-7-methoxy-2,3-dihydrobenzofuran-2-yl]-2,6-dimethoxy-phenol] and a monocyclic gamma-pyrone, zanthopyranone [3,5-dimethoxy-2-methyl-pyran-4-one], together with 28 known compounds were isolated from the stem wood of Formosan Zanthoxylum simulans. Their structures were determined through spectral analyses. Among the isolates, 11 compounds showed anti-platelet aggregation activity in vitro.

Alkaloids↗
PubMed2000

Biotransformation of the Trichoderma metabolite 6-n-pentyl-2H-pyran-2-one by cell suspension cultures of Pinus radiata.

Cell suspension cultures of Pinus radiata metabolize the antifungal Trichoderma secondary metabolite 6-n-pentyl-2H-pyran-2-one (6PAP) (1) via hydroxylation of the pentyl side chain. Examination of the culture medium following dosing studies with 1 revealed that 79-85% of this bioactive compound had been metabolised after 144 h. At that time, 34-40% of the metabolized dose was recovered as a series of monohydroxylated isomers of 1, the principal metabolite being 5-(2-pyron-6-yl)pentan-5-ol (7).

Antifungal Agents↗
PubMed1997

Kava extract ingredients, (+)-methysticin and (+/-)-kavain inhibit voltage-operated Na(+)-channels in rat CA1 hippocampal neurons.

The action of synthetic kava pyrones, (+)-methysticin and (+/-)-kavain, on voltage-operated Na(+)-channels was studied in whole-cell patch-clamped CA1 hippocampal neurons. In doses of 1-400 microM, both compounds exerted a rapid and reversible inhibition of the peak amplitude of Na(+)-currents. Shifting holding membrane potential (Vhold) to more positive values enhanced their blocking effect. The drugs studied did not demonstrate use-dependent properties at 10 Hz stimulation but shifted H infinity curve toward more negative potentials, accelerated time-course of inactivation and slowed down the recovery from inactivation. Voltage-dependence of Na(+)-channel inhibition can be explained by interaction of (+)-methysticin and (+/-)-kavain with resting closed and inactivated states of Na(+)-channel.

Animals↗
PubMed2003

Why B-ring is the active center for genistein to scavenge peroxyl radical: a DFT study.

The structure-activity relationship for genistein to scavenge peroxyl radical was clarified by density functional theory (DFT) calculations using the B3LYP/6-31G(d,p) method. It was revealed that the conjugation of an electron-withdrawing 1,4-pyrone group with A-ring of genistein was not beneficial to enhance the radical-scavenging activities. Thus, hydroxyl in B-ring became the active center of genistein to scavenge peroxyl radical.

Free Radical Scavengers↗
PubMed2000

Structural control of polyketide formation in plant-specific polyketide synthases.

BACKGROUND: Polyketide synthases (PKSs) generate molecular diversity by utilizing different starter molecules and by controlling the final length of the polyketide. Although exploitation of this mechanistic variability has produced novel polyketides, the structural foundation of this versatility is unclear. Plant-specific PKSs are essential for the biosynthesis of anti-microbial phytoalexins, anthocyanin floral pigments, and inducers of Rhizobium nodulation genes. 2-Pyrone synthase (2-PS) and chalcone synthase (CHS) are plant-specific PKSs that share 74% amino acid sequence identity. 2-PS forms the triketide methylpyrone from an acetyl-CoA starter molecule and two malonyl-CoAs. CHS uses a p-coumaroyl-CoA starter molecule and three malonyl-CoAs to produce the tetraketide chalcone. Our goal was to elucidate the molecular basis of starter molecule selectivity and control of polyketide length in this class of PKS. RESULTS: The 2.05 A resolution crystal structure of 2-PS complexed with the reaction intermediate acetoacetyl-CoA was determined by molecular replacement. 2-PS and CHS share a common three-dimensional fold, a set of conserved catalytic residues, and similar CoA binding sites. However, the active site cavity of 2-PS is smaller than the cavity in CHS. Of the 28 residues lining the 2-PS initiation/elongation cavity, four positions vary in CHS. Point mutations at three of these positions in CHS (T197L, G256L, and S338I) altered product formation. Combining these mutations in a CHS triple mutant (T197L/G256L/S338I) yielded an enzyme that was functionally identical to 2-PS. CONCLUSIONS: Structural and functional characterization of 2-PS together with generation of a CHS mutant with an initiation/elongation cavity analogous to 2-PS demonstrates that cavity volume influences the choice of starter molecule and controls the final length of the polyketide. These results provide a structural basis for control of polyketide length in other PKSs, and suggest strategies for further increasing the scope of polyketide biosynthetic diversity.

Acyl Coenzyme A↗
PubMed2003

Metal complexes of the trans-influencing ligand thiomaltol.

The wide use of the ligand 3-hydroxy-2-methyl-4-pyrone (maltol) in bioinorganic chemistry has prompted an effort to further exploit this ligand class by achieving an efficient, one-step synthesis of the chelator 3-hydroxy-2-methyl-4-thiopyrone (thiomaltol). Complexes of thiomaltol with nickel(II) and iron(III) have been prepared and studied by using UV-visible spectroscopy and electrochemical methods. In addition, both complexes as well as the free thiomaltol ligand have been structurally characterized by using single-crystal X-ray diffraction methods. The ligand is found to exert a strong trans influence on the structure of the complexes in the solid state with the nickel(II) and iron(III) complexes demonstrating a cis and fac geometry, respectively. The compounds described here should significantly expand the scope and utility of O,S-donor ligands derived from maltol and related precursors.

Crystallography, X-Ray↗
PubMed2005

Vanadium complexes with mixed O,S anionic ligands derived from maltol: synthesis, characterization, and biological studies.

Four mixed O,S binding bidentate ligand precursors derived from maltol (3-hydroxy-2-methyl-4-pyrone) have been chelated to vanadium to yield new bis(ligand)oxovanadium(IV) and tris(ligand)vanadium(III) complexes. The four ligand precursors include two pyranthiones, 3-hydroxy-2-methyl-4-pyranthione, commonly known as thiomaltol (Htma), and 2-ethyl-3-hydroxy-4-pyranthione, commonly known as ethylthiomaltol (Hetma), as well as two pyridinethiones, 3-hydroxy-2-methyl-4(H)-pyridinethione (Hmppt) and 3-hydroxy-1,2-dimethyl-4-pyridinethione (Hdppt). Vanadium complex formation was confirmed by elemental analysis, mass spectrometry, and IR and EPR (where possible) spectroscopies. The X-ray structure of oxobis(thiomaltolato)vanadium(IV),VO(tma)(2), was also determined; both cis and trans isomers were isolated in the same asymmetric unit. In both isomers, the two thiomaltolato ligands are arranged around the base of the square pyramid with the V=O linkage perpendicular; the vanadium atom is slightly displaced from the basal plane [V(1) = 0.656(3) A, V(2) = 0.664(2) A]. All of the new complexes were screened for insulin-enhancing effectiveness in streptozotocin-induced diabetes in rats, and VO(tma)(2) was profiled metabolically for urinary vanadium and ligand clearance by GFAAS and ESIMS, respectively. The new vanadium complexes did not lower blood glucose levels acutely, possibly because of rapid dissociation and excretion.

Animals↗
PubMed2003

Total synthesis of (+)-asteltoxin.

A convergent synthesis of (+)-asteltoxin (1) has been achieved by the Horner-Emmons olefination of bis(tetrahydrofuran) aldehyde 53 and alpha-pyrone phosphonate 5. A key step features the stereoselective construction of a sterically congested quaternary center embedded in the densely functionalized bis(tetrahydrofuran) subunit by a Lewis acid-catalyzed, pinacol-type rearrangement of an epoxy silyl ether. This pivotal rearrangement methodology parallels the proposed biosynthetic pathway of 1 and is ripe for applications to the stereocontrolled synthesis of structurally complex natural products.

Aspergillus↗
PubMed2004

New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups.

In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs), several new zinc-binding groups (ZBGs) based on pyrone, pyrothione, hydroxypyridinone, and hydroxypyridinethione chelators have been examined. Structural studies with tris(pyrazolyl)borate model complexes show that these ligands bind to the MMP active site zinc(II) ion in a bidentate fashion, similar to that found with hydroxamate-based inhibitors. Fluorescence- and colorimetric-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-3; mixed O,S-donor ligands were found to be remarkably potent, with IC50 values as much as 700-fold lower than that found for acetohydroxamic acid. Inhibitory activity was found to parallel metal binding affinity as determined in titrations with model complexes. These results demonstrate that MPIs based on new ZBGs are feasible and may indeed improve the overall performance of inhibitors designed against these important medicinal targets.

Hydroxamic Acids↗
PubMed2006

Structure assignment of lagunapyrone B by fluorous mixture synthesis of four candidate stereoisomers.

Techniques of fluorous mixture synthesis have been used to make four candidate stereoisomers for the natural product lagunapyrone B. A quasiracemic mixture of vinyl iodides whose component configurations at C19-21 were encoded by fluorous silyl groups was fused to a central fragment by a Negishi coupling. A separate quasiracemic mixture of pyrone fragments whose component configurations at C6,7 were also encoded by fluorous silyl groups was synthesized and demixed. Stille coupling of the resulting pure quasienantiomers with the quasiracemic mixture provided two quasi-diastereomeric samples, which were demixed and detagged to provide all four lagunapyrone B stereoisomers. Lagunapyrone was assigned the 6R,7S,19S,20S,21R configuration by comparison of optical rotations.

Alkenes↗
PubMed2001

Impact of competitive fungi on Trichothecene production by Fusarium graminearum.

Bioassays were used to determine the production of the trichothecene mycotoxin, deoxynivalenol (DON), by two isolates of Fusarium graminearum when grown in association with potentially competitive fungi and an antifungal chemical, 6-pentyl-alpha-pyrone (6PAP). The presence of 6PAP in the culture medium reduced DON production by as much as 80%, but this effect was reduced for the F. graminearum isolate that most efficiently metabolized the added 6PAP. A 6PAP-producing Trichoderma isolate grown in a competition assay system with the F. graminearum isolates was also able to substantially reduce DON production. When Fusarium isolates (F. crookwellense, F. culmorum, F. subglutinans, F. poae, F. equiseti, F. avenaceum, and F. sambucinum), which co-occur with F. graminearum in New Zealand maize plants (Zea mays), were grown in competition assays, the effect on DON production was variable. However, all isolates of F. subglutinans tested were shown to cause reductions in DON production (by 13-76%, mean = 62%). F. subglutinans frequently co-occurs with F. graminearum, but its presence can vary with location and time of the season. When the competitive fungus tested was also a trichothecene producer (e.g., of nivalenol), both toxins were produced in the assay medium. The results indicate that mycotoxin production by F. graminearum can be affected by the presence of particular competitive fungi. These results have implications for an ecological understanding of pathogenicity and of mycotoxin accumulation in plants. Early establishment of F. subglutinans, for example, may act as a biological control mechanism providing a temporary protection against invasion by more commonly toxigenic fusaria such as F. graminearum.

Fungicides, Industrial↗
PubMed2002

New monascus metabolite isolated from red yeast rice (angkak, red koji).

Red yeast rice (angkak, red koji) obtained as cultures of Monascus purpureus on rice was extracted and analyzed by HPLC. In addition to the known red, orange, and yellow pigments and the mycotoxin citrinin, a new Monascus metabolite was detected. It is present in the original red yeast rice and formed in higher amounts when red yeast rice is heated. High-resolution mass spectrometry indicated the molecular formula C(15)H(12)O(4). The chemical structure was elucidated by analysis of NMR data. The new compound, named monascodilone, is characterized by a propenyl group on a pyrone ring, an aromatic ring, and a gamma-lactone group.

Ascomycota↗
PubMed1986

Structure-activity study of 6-substituted 2-pyranones as inactivators of alpha-chymotrypsin.

A series of 2-pyranones, bearing halogens or electron-withdrawing groups at the 6-position and alkyl, aryl, or aralkyl groups at positions 3, 4, and 5, were synthesized to investigate their binding to and inactivation of chymotrypsin. Both binding and inactivation by 2-pyranones are sensitive to substitutions on positions 3, 4, 5, and 6. Binding was poorest with alkyl substituents on position 3 and best with phenyl substitution, with benzyl or benzyl-like substitution falling in between. The sequence of binding of 6-substituted pyrones is Cl greater than Br greater than H greater than CF3. 6-Chloro-2-pyranones bearing 4-phenyl or 3-(2-naphthylmethyl) substituents effected rapid inactivation of chymotrypsin, while those having 3-benzyl or 3-(1-naphthylmethyl) substituents gave slow inactivation and those with 3-phenyl or 3-alkyl substituents gave no inactivation. Only the 6-halopyrones demonstrated inactivation, with chloro-substituted ones acting faster than bromo-substituted ones.

Chymotrypsin↗
PubMed1986

5-(Halomethyl)-2-pyranones as irreversible inhibitors of alpha-chymotrypsin.

A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mechanism-based inhibitor. 3-Benzyl-5-(chloromethyl)-2-pyranone (3) and 3-(1-naphthylmethyl)-5-(chloromethyl)-2-pyranone (4) rapidly and irreversibly inactivate chymotrypsin with high efficiency (I/E = 2.0 for 3 and 1.38 for 4). However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis.

Alkylation↗
PubMed1996

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships.

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.

Anti-HIV Agents↗
PubMed2002

Synthesis of furano[2,3-c]pyran-3-one and thieno[2,3-c]pyran-3-one derivatives through the coupling of 3-alkynyl-2-heteroaromatic carboxaldehydes with Fischer carbene complexes: total synthesis of a Baccharis-derived cadinene derivative.

The coupling of Fischer carbene complexes with 3-alkynyl-2-heteroaromatic carboxaldehyde derivatives has been examined. The reaction affords pyrones fused to furans or thiophenes in a single step. The compounds are stable enough for isolation. If the carbene complex features a remote alkene substituent, a subsequent Diels-Alder reaction can occur. This reaction has been used as the key step in the synthesis of a naturally occurring cadinene derivative.

Aldehydes↗